title: Prolongation of cardiac ventricular repolarization under paliperidone: how and how much?
abstract: BACKGROUND
  Paliperidone (9-hydroxyrisperidone) is a second-generation antipsychotic. As observed with risperidone, QT interval prolongation was reported with paliperidone.
  
  
  OBJECTIVE
  The aim was to evaluate the effects of paliperidone on cardiac ventricular repolarization.
  
  
  METHODS
  (1) Patch-clamp experiments: Human ether-a-go-go-related gene (HERG)- or KCNQ1 + KCNE1-transfected cells were exposed to 0.1-100 μmol/L paliperidone (N = 39 cells, total) to assess the drug effect on HERG and KCNQ1 + KCNE1 currents. (2) Langendorff perfusion experiments: Hearts isolated from male Hartley guinea pigs (N = 9) were exposed to 0.1 μmol/L paliperidone to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization. (3) In vivo cardiac telemetry experiments: Guinea pigs (N = 8) implanted with transmitters were injected a single intraperitoneal dose of 1 mg/kg of paliperidone, and 24-hour electrocardiogram recordings were made.
  
  
  RESULTS
  (1) The estimated concentration at which 50% of the maximal inhibitory effect is observed (IC(50)) for paliperidone on HERG current was 0.5276 μmol/L. In contrast, 1 μmol/L paliperidone had hardly any effect on KCNQ1 + KCNE1 current (4.0 ± 1.6% inhibition, N = 5 cells). (2) While pacing the hearts at cycle lengths of 150, 200, or 250 milliseconds, 0.1 μmol/L paliperidone prolonged monophasic action potential duration measured at 90% repolarization by, respectively, 6.1 ± 3.1, 9.8 ± 2.7, and 12.8 ± 2.7 milliseconds. (3) Paliperidone (1 mg/kg) intraperitoneal caused a maximal 15.7 ± 5.3-millisecond prolongation of QTc.
  
  
  CONCLUSIONS
  Paliperidone prolongs the QT interval by blocking HERG current at clinically relevant concentrations and is potentially unsafe.
authors.affiliation: Faculté de Pharmacie, Université Laval, Québec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vigneault
authors.forename: Nisrin
authors.initials: N
authors.lastname: Kaddar
authors.forename: Sarah
authors.initials: S
authors.lastname: Bourgault
authors.forename: Bertrand
authors.initials: B
authors.lastname: Caillier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pilote
authors.forename: Dany
authors.initials: D
authors.lastname: Patoine
authors.forename: Chantale
authors.initials: C
authors.lastname: Simard
authors.forename: Benoit
authors.initials: B
authors.lastname: Drolet
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016466:CHO Cells; D002304:Cardiac Pacing, Artificial; D006224:Cricetinae; D003412:Cricetulus; D018492:Dopamine Antagonists / Q000009:adverse effects*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006168:Guinea Pigs; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000008:administration & dosage / Q000009:adverse effects*; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008297:Male; D000068882:Paliperidone Palmitate; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000009:adverse effects*; D018754:Ventricular Dysfunction / Q000139:chemically induced*
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007555:Isoxazoles; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D011743:Pyrimidines; D011994:Recombinant Proteins; D058830:Serotonin 5-HT2 Receptor Antagonists; D000068882:Paliperidone Palmitate